CN102803256B - Method for preparing (r)-3-(3-fluoro-4-(1-methyl-5,6-dihydro-1,2,4-triazin-4(1h)-yl)phenyl)-5-(substituted methyl)oxazolidin-2-one derivatives - Google Patents
Method for preparing (r)-3-(3-fluoro-4-(1-methyl-5,6-dihydro-1,2,4-triazin-4(1h)-yl)phenyl)-5-(substituted methyl)oxazolidin-2-one derivatives Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
- C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
The present invention relates to a method for preparing (R)-3-(3-fluoro-4-(1-methyl-5,6-dihydro-1,2-4-triazin-4(1H)-yl)phenyl)-5-(substituted methyl)oxazolidin-2-one derivatives, which are oxazolidinone antibiotic compounds having a cyclic amidrazone group, and to intermediates thereof, and uses 3,4-difluoro-4-nitrobenzen as a starting material. According to the preparation method of the present invention, (R)-3-(3-fluoro-4-(1-methyl-5,6-dihydro-1,2-4-triazin-4(1H)-yl)phenyl)-5-(substituted methyl)oxazolidin-2-one derivatives, which are compounds that are useful as oxazolidinone antibiotics, can be prepared in high purity and high yield in a simpler manner than conventional methods.
Description
Technical field
The present invention relates to (R)-3-(the fluoro-4-of 3-(1-methyl-5 that a kind of following chemical formula 1 represents, 6-dihydro-1,2,4-triazine-4 (1H)-Ji) phenyl) Preparation Method And Their Intermediate of-5-(substituent methyl) oxazolidine-2-ketone derivatives, described (R)-3-(the fluoro-4-of 3-(1-methyl-5,6-dihydro-1,2,4-triazine-4 (1H)-Ji) phenyl)-5-(substituent methyl) oxazolidine-2-ketone derivatives is the oxazolidinones Antibiotique composition with cyclic amino hydrazone group.
[chemical formula 1]
[described R is-OH or-NHC (=O) R
1, R
1(C1-C6) alkyl or (C1-C6) alkoxyl group.]
Background technology
There is compound 1a ((R)-3-(the fluoro-4-of 3-(1-methyl-5 of having structure, 6-dihydro-1,2,4-triazine-4 (1H)-Ji) phenyl)-5-(methylol) oxazolidine-2-ketone) as oxazolidinones microbiotic, may be used for treating gram-positive microorganism, especially methicillin-resistant staphylococcus aureus (Methicillin-resistant Staphylococcusaureus, MRSA), the infection of vancomycin resistant enterococci (vancomycin-resistant enterococci, VRE) etc.
The application number applied for the present inventor is announced described compound in the Korean Patent of 10-2008-0093712 as antibiotic drug effect and preparation method.But, because W-response step is long, need to use column chromatography in for the most purified operation of each step, be therefore not suitable for a large amount of production.
Summary of the invention
The technical problem that invention will solve
Therefore, the object of the present invention is to provide (R)-3-(the fluoro-4-of 3-(1-methyl-5, 6-dihydro-1, 2, 4-triazine-4 (1H)-Ji) phenyl) preparation method of-5-(substituent methyl) oxazolidine-2-ketone derivatives, described method is by reducing W-response step, be used in separation and purification process the crystallization process or extraction process etc. that are applicable to industry size synthesis, compare reference technique simpler, economically prepare highly purified (R)-3-(the fluoro-4-of 3-(1-methyl-5, 6-dihydro-1, 2, 4-triazine-4 (1H)-Ji) phenyl)-5-(substituent methyl) oxazolidine-2-ketone derivatives.
In addition, another object of the present invention is to provide preparation (R)-3-(the fluoro-4-of 3-(1-methyl-5,6-dihydro-1,2,4-triazine-4 (1H)-Ji) phenyl)-5-(substituent methyl) oxazolidine-2-ketone derivatives use prepare intermediate and preparation method thereof.
The technique means of technical solution problem
The present invention relates to one (R)-3-(the fluoro-4-of 3-(1-methyl-5,6-dihydro-1,2,4-triazine-4 (1H)-Ji) phenyl) Preparation Method And Their Intermediate of-5-(substituent methyl) oxazolidine-2-ketone derivatives, described (R)-3-(the fluoro-4-of 3-(1-methyl-5,6-dihydro-1,2,4-triazine-4 (1H)-Ji) phenyl)-5-(substituent methyl) oxazolidine-2-ketone derivatives is be used as the compound of the antibiotic chemical formula 1 of oxazolidinones.
In addition, the compound of following chemical formula 1 can also be made into the salt of various form, and the present invention also comprises the salt of these forms.The method goes for industry size, especially, comprises the novel synthesis preparing cyclic amino hydrazone group (amidrazone group) according to the preparation method of the compound of chemical formula 1 of the present invention.In addition, in order to the chemical preparation process of applicable industry size, the present invention includes the intermediate of the advantage of cost-efficient crystallization or the preparation method of its additive salt,
[chemical formula 1]
[described R is-OH or-NHC (=O) R
1, R
1(C1-C6) alkyl or (C1-C6) alkoxyl group.]
The preparation method of the compound of described chemical formula 1 shown in following reaction formula 1.
[reaction formula 1]
[R is-OH or-NHC (=O) R
1, R
1be (C1-C6) alkyl or (C1-C6) alkoxyl group, R' is (C1-C6) alkyl or (C6-C12) aryl (C1-C6) alkyl]
As shown in following reaction formula 2, the compound of preparative chemistry formula IV respectively, the compound of described chemical formula IV is the starting material of the compound for the preparation of chemical formula 1 of the present invention.
[reaction formula 2]
[X is halogen, substituted or unsubstituted (C1-C6) alkylsulfonyloxy (alkanesulfonyloxy) or substituted or unsubstituted (C6-C12) aryl-sulfonyl oxygen (arylsulfonyloxy).]
The invention provides a kind of oxazole alkanones derivative of chemical formula 1 or the preparation method of its pharmacologically acceptable salt, described oxazole alkanones derivative has cyclic amino hydrazone group, as described in shown in reaction formula 1 and reaction formula 2, described method comprises the following steps:
Step 1) 3,4-difluoro nitrobenzene and thanomin are reacted, with the compound of preparative chemistry formula I;
Step 2) compound of chemical formula I is reacted with the reagent (agent) containing leaving group X, the alcohol radical of the compound of chemical formula I is converted to leaving group X, thus the compound (step 2-1) of preparative chemistry formula II-1, or deposit in case at alkali, the compound of chemical formula I is reacted, with the aziridine cpd (step 2-2) of preparative chemistry formula II-2;
Step 3) compound of the compound of chemical formula II-1 or chemical formula II-2 and methyl hydrazine are reacted, with the compound of preparative chemistry formula III;
Step 4) compound of chemical formula III and trimethyl orthoformate are reacted, with the cyclic amino hydrazone compound of preparative chemistry formula IV;
Step 5) nitro of cyclic amino hydrazone compound of reduction chemical formula IV, with the amine compound of preparative chemistry formula V;
Step 6) amine compound of chemical formula V and carbonyl dimidazoles and R'-OH [R'=(C1-C6) alkyl or (C6-C12) aryl (C1-C6) alkyl] are reacted successively, convert the amido of chemical formula V to carbamate, thus the compound of preparative chemistry formula VI;
Step 7) compound of cyclisation chemical formula VI, with the Oxazolidinone compound of preparative chemistry formula 1.
Hereafter, each step is described in detail.
The preparation of the compound of [step 1] chemical formula I
In order to prepare the compound represented by chemical formula I, return stirring starting material 3,4-difluoro nitrobenzene and thanomin in organic solvent.In this case, the example of spendable solvent comprises nitrile (such as, acetonitrile etc.), alcohols (such as, ethanol, Virahol etc.), ester class (such as, tetrahydrofuran (THF), diisopropyl ether, dioxan, 1,2-glycol dimethyl ether etc.), arene (such as, benzene, toluene etc.), amides (such as N,N-DIMETHYLACETAMIDE, dimethyl formamide etc.), but the present invention is not limited to these inert solvents, these solvents can be used alone, also can be used in combination.Be preferably acetonitrile, Virahol, dioxan etc., be more preferably acetonitrile.
According to the usage quantity of thanomin, described reaction can be carried out under alkali presence or absence condition.For 3,4-difluoro nitrobenzenes of 1 equivalent, when the thanomin of use 1 equivalent, preferably use alkali, and when excessive thanomin more than use 1 equivalent, can not alkali be used.Use in the reaction of excessive thanomin, the usage quantity of thanomin is preferably 1.5 equivalent to 3 equivalents, in this case, operable alkali is the organic bases of such as triethylamine or diethyl isopropyl amine or the mineral alkali for such as salt of wormwood and sodium carbonate, preferably in the scope of 1.1 equivalent to 2 equivalents.
The preparation of the compound of [step 2] chemical formula II-1 or the compound of chemical formula II-2
By making the compound represented by chemical formula I react with the reagent (agent) containing leaving group X, the alcohol radical of the compound of chemical formula I being converted to leaving group X, obtaining the compound of chemical formula II-1.As suitable leaving group, when leaving group X represents halogen atom, X is chlorine atom, bromine atoms or atomic iodine.When leaving group X represents sulfonyloxy, the example of leaving group preferably includes substituted or unsubstituted (C1-C6) alkylsulfonyloxy (such as, methanesulfonyloxy group, ethanesulfonyl oxygen base or trifluorometanesulfonyloxy) or substituted or unsubstituted (C6-C12) aryl-sulfonyl oxygen is (such as, phenylsulfonyloxy, p-tosyloxy, p-bromophenylsulfonyloxy, p-nitrobenzenesulfonyloxy), but be not limited thereto.Alcohol radical is converted to leaving group, and such as, chlorine, bromine, methylsulfonic acid, tosylate, benzene sulfonate are well known in the art.Preferably in the non-polar organic solvent of such as methylene dichloride, carry out described reaction, and the salt used is preferably the amine of such as triethylamine.
By depositing in case at triphenylphosphine and alkali, stirring the compound more than 12 hours represented by chemical formula I, and being about 72 hours most, carrying out the compound of preparative chemistry formula II-2.The alkali used in this reaction most preferably is triethylamine, solvent can use such as tetrahydrofuran (THF) (THF, Tetra Hydro Furan) ester (ether) class or most non-polar solvent, preferably use the mixture of THF and tetrachloromethane.
The preparation of the compound of [step 3] chemical formula III
Reacted by the compound and methyl hydrazine that make the compound of chemical formula II-1 or chemical formula II-2, obtain the compound of chemical formula III.In this case, operable solvent is the various polar organic solvents of the alcohols of such as ethanol etc., during the compound of the chemically compound preparative chemistry formula III of formula II-2, tool has the following advantages: can omit purification procedures in the reaction of chemical formula II-2, and added in reaction vessel by methyl hydrazine, thus obtain the compound of chemical formula III immediately.
In reaction, the usage quantity of methyl hydrazine is preferably 5 equivalent to 10 equivalents, and temperature of reaction is preferably 20 DEG C to 80 DEG C.
The preparation of the compound of [step 4] chemical formula IV
Generate cyclic amino hydrazone ring by the compound of chemically formula III, obtain the compound of chemical formula IV.Can by making the compound of chemical formula III and ortho-formiate (orthoformate) react in acetic acid, or by utilizing formic acid etc. to carry out cyclization thing after formylation to the compound of chemical formula III, carry out described reaction.Preferably, by using acetic acid as solvent, the compound of return stirring chemical formula III and excessive trimethyl orthoformate (trimethyl orthoformate), obtain the compound of chemical formula IV.More preferably, the acetic acid of mix with the trimethyl orthoformate of 2 equivalent to 10 equivalents 20% to 50% can be used as solvent.
The preparation of the compound of [step 5] chemical formula V
By the nitro of the cyclic amino hydrazone compound of reduction chemical formula IV, obtain the amine compound represented by chemical formula V.In this reaction, the example of operable solvent comprises alcohols (such as, methyl alcohol, ethanol, propyl alcohol etc.) or ester class (such as, tetrahydrofuran (THF), diisopropyl ether, dioxan, 1,2-glycol dimethyl ether etc.).The reduction of this nitro is known, can use metal (such as in acid condition, zinc, iron, tin, tin chloride etc.), or hydrogenation can be carried out by using the transition metal such as Raney's nickel, palladium carbon as catalyzer, carry out described reduction reaction.Preferably, by using palladium carbon as catalyzer in alcoholic solvent, stirring under an atmosphere of hydrogen, described reduction reaction can be carried out.
The preparation of the compound of [step 6] chemical formula VI
After reacting by making the amino of chemical formula V and carbonyl dimidazoles (carbonyl diimidazole), utilizing alcohol or alkoxide to process, obtaining the carbamate compounds represented by chemical formula VI.In addition, in the present reaction, can chloroformate derivative or carbonyl chloride etc. be used, because poisonous being unsuitable for is used in a large amount of production, although also can carbonate derivative be used, but there is reactive weak shortcoming.Therefore, in the present invention, preferably carbonyl dimidazoles is used.
In this reaction, the example of operable alcohol R'-OH [R' is (C1-C6) alkyl or (C6-C12) aryl (C1-C6) alkyl] is preferably alkyl alcohols or the benzylalcohol class of such as methylol, ethyl alcohol, propyl group alcohol.In addition, in the present reaction, the mixture of alcohol and alkoxide can be used.In this case, reaction can more promptly be carried out and at room temperature terminate immediately.Preferably, by using ethanol as solvent, at room temperature can add ethyl alkoxide, or by heating in alcohol solvent, carrying out described reaction.
The preparation of the compound of [step 7] chemical formula 1
Chemically the various methods of the Oxazolidinone compound of the carbamate compounds synthetic chemistry formula 1 of formula VI are known.Herein, diverse ways can be selected according to the R base of chemical formula 1.The example of this reaction shown in following reaction formula 3, and reaction formula 3 is only an example of this reaction, and the present invention is not limited to this.
[reaction formula 3]
As shown in above-mentioned reaction formula 3, suitable method can be selected according to the kind of the substituent R of chemical formula 1.Such as; when R is the compound 1a of hydroxyl (-OH); be applicable to using (R)-Glycidyl butyrate ((R)-glycidyl butyrate); in the compound 1b situation that R is N-ethanoyl, be applicable to using (S)-N-(the bromo-2-acetyloxypropyl of 3-) ethanamide ((S)-N-(3-bromo-2-acetoxypropyl) acetamide).Especially, it is well-known that the synthetic method of compound 1b has a variety of, especially recently application patent EP 2072513 A1, EP 2072514 A1, EP 2141161 A1, EP 2141162 widely use in A1, and disclose detailed experimental technique wherein.In addition, when R is the compound 1c of carbamate, epoxy ethyl carbamate (oxiranylcarbamate) compound can be used.
In addition, as shown in following reaction formula 4, all these compounds can be synthesized from compound 1a.
[reaction formula 4]
As described in shown in reaction formula 4, the compound of chemical formula 1 also can make the various derivatives of such as compound 1b or compound 1c from compound 1a.Especially, the such as carbamate compounds of compound 1c more preferably uses described method to synthesize.
The alkali used in the synthesis of compound 1a can be butyllithium or trimethyl carbinol lithium, preferably uses trimethyl carbinol lithium.The solvent used in reaction can be THF or dimethyl formamide (DMF, DimethylFormamide), preferably uses the mixture of THF and DMF.More preferably THF and DMF is used with the ratio of 2:1.
Synthetic compound 1b and compound 1c in the following manner: add the triphenylphosphine being respectively 1.3 equivalents and diisopropyl azodiformate (DIAD), diphenyl phosphate azide (DPPA) in THF solvent, after obtained azido cpd, utilize Pd/C catalyzer hydrogenation azido cpd, prepare amine compound.The amine compound obtained like this if make and Ac
2o reacts, then obtained compound 1b, and if after making the carbonyl dimidazoles of amine compound and 2 equivalent to 3 equivalents react, add the methylate of 1 equivalent in methanol solvate, then obtained compound 1c.
The derivative of chemical formula 1 also can make the salt of various form, and in this case, possible salt comprises all pharmacologically acceptable salts.Pharmacologically acceptable salt comprises the acid salt formed by pharmaceutically useful free acid (free acid).Described free acid can use mineral acid and organic acid, the mineral acid used is hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid etc., and the organic acid used is citric acid, acetic acid, lactic acid, toxilic acid, fumaric acid, glyconic acid, methylsulphonic acid, oxyacetic acid, succsinic acid, 4-toluenesulphonic acids, trifluoroacetic acid, galacturonic acid, embonic acid, paddy amino acid and aspartic acid etc.In addition, the present invention includes the hydrate of the salt of described oxazole alkanones derivative, especially, under described salt has hygroscopic situation, use there is the salt of crystalline hydrate forms can be very effective.
Its functional replacement as known in the art or derivative can be used to substitute the solvent or reagent used in the present invention, the reaction conditions such as reaction times and temperature of reaction can be adjusted to optimize reaction.Similar with the present invention, can from Reaction Separation resultant, in some cases, and can according to extraction, the other purifying resultant of common method in this areas such as crystallization and grinding (trituration).
Beneficial effect
As mentioned above, the present invention relates to a kind of preparation method as the antibiotic oxazole alkanones derivative for resistant organisms such as MRSA, VRE.In addition, comprise cyclic amino hydrazone group due to compound of the present invention thus the form of salt can be made, therefore comparing existing known compound, there is high water solubility, thus easily can develop this compound as oral pharmaceutical or injection.
Preparation method according to the oxazole alkanones derivative or its pharmaceutically useful salt with cyclic amino hydrazone group of the present invention improves overall yield, and use is separated and the crystallization process of applicable industry size synthesis in purification process or extraction process etc., compared to existing technology economically with (R)-3-of industry size synthesis of high purity (the fluoro-4-of 3-(1-methyl-5,6-dihydro-1,2,4-triazine-4 (1H)-Ji) phenyl)-5-(substituent methyl) oxazolidine-2-ketone derivatives.
Embodiment
Hereafter, in order to help to understand the present invention, preferred embodiment and experimental example are shown.But, the following example and experimental example provide only for more easily understanding the present invention, the following example does not limit content of the present invention.
Compound 1a{ (R)-3-(the fluoro-4-of 3-(the 1-methyl-5 of [embodiment 1] chemical formula 1,6-dihydro-1,2,4-triazine-4 (1H)-Ji) phenyl)-5-(methylol) oxazolidine-2-ketone preparation
the preparation of chemical compounds I
After 3,4-difluoro nitrobenzene (product of 158g, 0.99mol, Aldrich company) is dissolved in acetonitrile (800mL), add thanomin (117g, 1.9mol) and return stirring 4 hours.After described reactant is cooled to room temperature, concentrating under reduced pressure also utilizes ether (diethylether) solidification (trituration) to filter afterwards, thus obtains yellow chemical compounds I (199g, 0.99mol, 100%).
1h NMR (one dimension hydrogen spectrum nucleus magnetic resonance) (400MHz, chloroform (chloroform)-d
1) δ=7.97 (d, J=8.8Hz, 1H), 7.87 (dd, J
1=11.6Hz, J
2=2.4Hz, 1H), 6.65 (t, J=8.8Hz, 1H), 5.10-4.87 (br s, 1H), 3.97-3.83 (m, 2H), 3.43-3.37 (m, 2H)
LCMS (LC-MS): for C
8h
9-FN
2o
3, 201 (M+H
+)
the preparation of compound ii-1 (X=OMs)
After chemical compounds I (37.7g, 188mmol) is dissolved in methylene dichloride (400mL), at 0 DEG C, add triethylamine (TEA, Tri Ethyl Amine) (39.7mL, 283mmol) and slowly add Ms-Cl (17.5mL, 226mmol).Stir after 30 minutes, utilize methylene dichloride (400mL) to dilute and utilize distilled water (500mL) to wash, and recycling methylene dichloride (400mL × 3) aqueous layer extracted.Utilize Na
2sO
4after dry organic layer, filter and concentrating under reduced pressure, thus obtain yellow solid compound II-1 (52.5g, 99%).
1H NMR(600MHz,chloroform-d
1)δ＝7.99(d,J＝9.0Hz,1H),7.90(dd,J
1＝11.4Hz,J
2＝2.4Hz,1H),6.67(t,J＝9.0Hz,1H),4.99(br s,1H),4.43(t,J＝5.4Hz,2H),3.65(q,J＝5.4Hz,2H),3.04(s,3H)
LCMS: for C
9h
11-FN
2o
5s, 279 (M+H
+)
the preparation of compound III
Compound ii-1 (52.5g, 188mmol) is added while also stirring in EtOH (300mL), add diisopropylethylamine (DIPEA, diisopropyl ethyl amine) (32.8mL, 188mmol) add the 40% methyl hydrazine aqueous solution (75mL, 570mmol), and return stirring 2 hours.Concentrating under reduced pressure solvent also utilizes methylene dichloride (400mL) to dilute, and utilizes sat. (saturated) NaHCO
3(400mL) wash.Utilize methylene dichloride (250mL) again after aqueous layer extracted, utilize Na
2sO
4after the dry organic layer collected, filter and concentrating under reduced pressure, thus obtain quantitative yellow solid compound III (42.9g, 100%).
1H NMR(600MHz,chloroform-d
1)δ＝7.99(dd,J
1＝9.0Hz,J
2＝2.4Hz,1H),7.86(dd,J
1＝11.4Hz,J
2＝2.4Hz,1H),6.61(t,J＝9.0Hz,1H),5.93(br s,1H),3.89(q,J＝5.4Hz,2H),2.99(br s,2H),2.72(t,J＝5.4Hz,2H),2.58(s,3H)
LCMS: for C
9h
13-FN
4o
2, 229 (M+H
+)
the preparation of compounds Ⅳ
Compound III (42.9g, 188mmol) is added in AcOH (200mL) and trimethyl orthoformate (206mL, 1.88mol), and return stirring 15 hours.Concentrating under reduced pressure solvent also, after utilizing ethyl acetate (700mL) to dilute, adds distilled water (500mL) and adds Na
2cO
3make the pH of solution for after about 8 to 9, utilize separating funnel to be separated organic layer.Recycling ethyl acetate (300mL) aqueous layer extracted also utilizes Na
2sO
4after the dry organic layer collected, utilize the pipe of the silicon-dioxide of filling the 5cm that has an appointment to filter, concentrating under reduced pressure, thus obtain red solid compound IV (34.5g, 77%).
1H NMR(400MHz,chloroform-d
1)δ＝8.07-7.99(m,2H),7.13(m,2H),3.93(m,2H),3.08(m,2H),2.83(s,3H)
LCMS: for C
10h
11-FN
4o
2, 239 (M+H
+)
the preparation of compound V
Compounds Ⅳ (34.5g, 145mmol) added MeOH (400mL) and after adding 10%Pd/C (10g), hydrogen balloon is arranged on flask, at room temperature stirring 4 hours.By utilizing celite filtration under diminished pressure to remove Pd/C and concentrating under reduced pressure filtrate, thus obtain orange solids compound V (29.3g, 97%).
1H NMR(600MHz,chloroform-d
1)δ＝6.92(t,J＝9.0Hz,1H),6.77(s,1H),6.44-6.39(m,2H),3.78(br s,2H),3.73(t,J＝4.8Hz,2H),2.94(t,J＝4.8Hz,2H),2.77(s,3H)
LCMS: for C
10h
13-FN
4, 209 (M+H
+)
compound VI (R'=-CH
2
cH
3
) preparation
Carbonyl dimidazoles (46g, 282mmol) is added while also stirring in methylene dichloride (400mL), slowly add compound V (29.3g, 141mmol).At room temperature stir this solution 3 hours and concentrating under reduced pressure until this solution remains about 200mL, add EtOH (200mL) and concentrating under reduced pressure again.Again EtOH (400mL) to be added in this solution and to heat 4 hours at 50 DEG C.After being cooled to room temperature, concentrating under reduced pressure, then utilizes ethyl acetate (400mL) to dilute, and adds 6N HCl until pH about 6.After being separated organic layer, utilize methylene dichloride (300mL × 6) aqueous layer extracted again.Utilize Na
2sO
4after the dry organic layer collected, filter and concentrating under reduced pressure, thus obtain compound as white solid VI (30.5g, 77%).
1H NMR(600MHz,chloroform-d
1)d＝7.40(br d,J＝12.6Hz,1H),7.03(t,J＝9.0Hz,1H),7.00(br dd,J
1＝9.0Hz,J
2＝1.8Hz,1H),6.88(s,1H),6.76(s,1H),4.23(q,J＝7.2Hz,2H),3.80(t,J＝4.8Hz,2H),2.97(t,J＝4.8Hz,2H),2.78(s,3H),1.31(t,J＝7.2Hz,3H)
LCMS: for C
13h
17-FN
4o
2, 281 (M+H
+)
the preparation of compound 1a
Compound VI (30.5g, 109mmol) is added while also stirring in the mixing solutions of THF (300mL) and DMF (150mL), slowly added MeOH (8.8mL, 218mmol) and tBuOLi (26.1g, 327mmol) at 0 DEG C in 10 minutes after, stir 20 minutes.(R)-Glycidyl butyrate (31.4mL, 218mmol) is added in this solution and also at room temperature stir 10 hours.By sat.NH
4cl (100mL) to add in this solution and utilizes 1N (equivalent) HCL to neutralize, and after concentrating under reduced pressure, utilizes ethyl acetate (400mL) to dilute and utilizes distilled water (300mL) to wash.Utilize methylene dichloride (300mL × 4) aqueous layer extracted again.Utilize Na
2sO
4after the dry organic layer collected, filter and concentrating under reduced pressure, and after utilizing hexane to solidify (trituration), utilize washed with diethylether.Again add this solid in Virahol after, while cooling, filter the solid generated, thus obtain compound as white solid 1a (22.5g, 67%).
1H NMR(600MHz,DMSO-d
6)d＝7.59(dd,J
1＝13.8Hz,J
2＝2.4Hz,1H),7.33-7.30(m,2H),6.84(s,1H),5.23(t,J＝5.4Hz,1H),4.70(m,1H),4.07(t,J＝9.0Hz,1H),3.82(m,1H),3.71(t,J＝4.8Hz,2H),3.69-3.54(m,2H),2.87(t,J＝4.8Hz,2H),2.61(s,3H)
LCMS: for C
14h
17-FN
4o
3, 309 (M+H
+)
The compound of chemical formula II-2 is used as the preparation method of intermediate by [embodiment 2]
Chemical compounds I (24.2kg, 121mol) is dissolved in after in THF (130kg), at 10 DEG C to 15 DEG C, adds triphenylphosphine (41kg, 156mol) and TEA (24.5kg, 242mol) and add CCl again
4(37.3kg), slowly rose to room temperature in 1 hour after, stir 1 day.Confirm after reaction terminates, carry out next step immediately.
At 10 DEG C to 15 DEG C, methyl hydrazine (44.5kg, 966mol) is added in above-mentioned reaction solution, and after stirring 5 hours, at room temperature stir 24 hours, and stir 10 hours at 35 DEG C to 40 DEG C.After confirming that reaction terminates, be cooled to room temperature and after add distilled water (100kg) while stirring, place and layer can be separated from each other.Be separated THF layer, after utilizing distilled water (50kg) to wash, utilize Na
2sO
4(20kg) dry 5 hours and filter, thus point two steps obtain compound III (11.5kg, 50mol) with productive rate 41%.
The preparation of the compound 1c of [embodiment 3] chemical formula 1
Compound 1a (7g, 22.7mmol) and triphenylphosphine (7.7g, 29.5mmol) are added while also stirring in tetrahydrofuran (THF) (100mL), diisopropyl azodiformate (DIAD is slowly added successively at 0 DEG C, diisopropyl azodiformate) (5.8mL, 29.5mmol) and diphenyl phosphate azide (DPPA, 5.1mL, 29.5mmol), and at room temperature stir 1.5 hours.50mL distilled water is added after in this solution, stir 5 minutes and concentrating under reduced pressure until solution remains about after half, utilize diluted ethyl acetate, and utilize sat.NaHCO
3washing.Utilize Na
2sO
4after dry organic layer, filter, concentrating under reduced pressure carry out silica filtration, thus obtain the azido cpd (6.1g, 81%) of white solid.
The azido cpd obtained like this (6.1g, 18.3mmol) is added in methyl alcohol (250mL) together with Pd/C (0.9g), and stirs 1.5 hours under hydrogen balloon.Filter this solution with celite and concentrate, thus obtaining quantitative amine compound.
After the amine compound obtained like this being dissolved in methylene dichloride (100mL), be added drop-wise to after in methylene dichloride (150mL) solution being dissolved with CDI (8.9g, 54.9mmol), at room temperature stir 30 minutes.Methyl alcohol (150mL) to be added in this solution and concentrating under reduced pressure, add the methyl alcohol of 400mL again and concentrating under reduced pressure until methyl alcohol only remains about 200mL, after removing methylene dichloride, add 1M (volumetric molar concentration) NaOMe (18.3mL) and at room temperature stir 1 hour.After this solution of concentrating under reduced pressure, after this solubilize is in ethyl acetate (100mL), add 100mL distilled water, and utilize 4N HCI to neutralize.Utilize methylene dichloride (300mL × 3) aqueous layer extracted again.Utilize Na
2sO
4after the dry organic layer collected, filter, concentrating under reduced pressure carry out silica filtration, thus obtain compound as white solid 1c (3kg, 45%).
1H NMR(400MHz,CDCl
3)d＝7.49(dd,J
1＝9.0Hz,J
2＝1.4Hz,1H),7.14(dd,J
1＝6.0Hz,J
2＝1.4Hz,1H),7.08(t,J＝6.0Hz,1H),6.87(s,1H),5.08(br t,1H),4.76(m,1H),4.01(t,J＝6.0Hz,1H),3.80-3.76(m,3H),3.66(s,3H),3.64-3.51(m,2H),2.96(t,J＝3.2Hz,2H),2.76(s,3H)
LCMS: for C
16h
20fN
5o
4, 366 (M+H
+)
Industrial usability
The present invention relates to a kind of preparation method as the antibiotic oxazole alkanones derivative for resistant organisms such as MRSA, VRE.In addition, comprise cyclic amino hydrazone group due to compound of the present invention thus the form of salt can be made, therefore comparing existing known compound, there is higher water solubility, thus easily can develop this compound as oral pharmaceutical or injection.
Preparation method according to the oxazole alkanones derivative or its pharmaceutically useful salt with cyclic amino hydrazone group of the present invention can improve overall yield, and use is separated and the crystallization process of applicable industry size synthesis in purification process or extraction process etc., comparing reference technique can economically with (R)-3-of industry size synthesis of high purity (the fluoro-4-of 3-(1-methyl-5,6-dihydro-1,2,4-triazine-4 (1H)-Ji) phenyl)-5-(substituent methyl) oxazolidine-2-ketone derivatives.
Claims (5)
1. have the Oxazolidinone compound of chemical formula 1 or the preparation method for its pharmacologically acceptable salt of cyclic amino hydrazone group, described method comprises:
Step 1): by making 3,4-difluoro nitrobenzene and thanomin react, the compound of preparative chemistry formula I;
Step 2): react with the reagent containing leaving group X by making the compound of chemical formula I, the alcohol radical of the compound of chemical formula I is converted to leaving group X, thus the compound of preparative chemistry formula II-1, or deposit in case at alkali, by making the compound of Formula I react, thus the aziridine cpd of preparative chemistry formula II-2;
Step 3): reacted by the compound and methyl hydrazine making the compound of chemical formula II-1 or chemical formula II-2, the compound of preparative chemistry formula III;
Step 4): reacted by the compound and trimethyl orthoformate making chemical formula III, the cyclic amino hydrazone compound of preparative chemistry formula IV;
Step 5): by the nitro of the cyclic amino hydrazone compound of reduction chemical formula IV, the amine compound of preparative chemistry formula V;
Step 6): the amine compound of chemical formula V and carbonyl dimidazoles and R'-OH are reacted successively, converts the amido of chemical formula V to carbamate, thus the compound of preparative chemistry formula VI;
Step 7): by the compound of cyclisation chemical formula VI, the Oxazolidinone compound of preparative chemistry formula 1,
[chemical formula 1]
[chemical formula I]
[chemical formula II-1]
[chemical formula II-2]
[chemical formula III]
[chemical formula IV]
[chemical formula V]
[chemical formula VI]
Wherein, X is halogen, C1-C6 alkylsulfonyloxy or C6-C12 aryl-sulfonyl oxygen, trifluorometanesulfonyloxy, p-tosyloxy, p-bromophenylsulfonyloxy, p-nitrobenzenesulfonyloxy, and R is-OH or-NHC (=O) R
1, R
1be C1-C6 alkyl or C1-C6 alkoxyl group, R' is C1-C6 alkyl or C6-C12 aryl C1-C6 alkyl.
2. the method for claim 1, further comprising the steps of:
Deposit in case at triphenylphosphine, diisopropyl azodiformate, diphenyl phosphate azide, after the compound of following chemical formula 1a is reacted, the amine compound that obtained by hydrogenation and Glacial acetic acid are reacted, thus the compound of preparative chemistry formula 1b
[chemical formula 1a]
[chemical formula 1b]
3. the method for claim 1, also comprises the steps:
Deposit in case at triphenylphosphine, diisopropyl azodiformate, diphenyl phosphate azide, after the compound of following chemical formula 1a is reacted, the amine compound that obtained by hydrogenation and carbonyl dimidazoles and C1-C6 alkoxide are reacted successively, thus the compound of preparative chemistry formula 1c
[chemical formula 1a]
[chemical formula 1c]
4. the cyclic amino hydrazone compound represented by following chemical formula IV,
[chemical formula IV]
5. the cyclic amino hydrazone compound represented by following chemical formula VI, [chemical formula VI]
R' is C1-C6 alkyl or C6-C12 aryl C1-C6 alkyl.
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| KR10-2010-0020525 | 2010-03-08 | ||
| KR1020100020525A KR101128029B1 (en) | 2010-03-08 | 2010-03-08 | Method for preparing of R-3-3-fluoro-4-1-methyl-5,6-dihydro-1,2,4-triazin-41H-ylphenyl-5-substituted methyloxazolidin-2-one derivatives |
| PCT/KR2011/001579 WO2011111971A2 (en) | 2010-03-08 | 2011-03-08 | Method for preparing (r)-3-(3-fluoro-4-(1-methyl-5,6-dihydro-1,2,4-triazin-4(1h)-yl)phenyl)-5-(substituted methyl)oxazolidin-2-one derivatives |
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| WO2003035648A1 (en) * | 2001-10-25 | 2003-05-01 | Astrazeneca Ab | Aryl substituted oxazolidinones with antibacterial activity |
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| WO2010036000A3 (en) * | 2008-09-24 | 2010-07-15 | Legochem Bioscience Ltd. | Novel oxazolidinone derivatives with cyclic amidoxime or cyclic amidrazone and pharmaceutical compositions thereof |
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| EP2141162A1 (en) | 2008-07-01 | 2010-01-06 | Ferrer Internacional, S.A. | 3-(n-heterocyclyl)-pyrrolidinyl-phenyl-oxazolidinones as antibacterial agents |
| EP2141161A1 (en) | 2008-07-01 | 2010-01-06 | Ferrer Internacional, S.A. | 3-cyanopyrrolidinyl-phenyl-oxazolidinones as antibacterial agents |
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